Trazodone for Obstructive Sleep Apnea

Overseen By Ludovico Messineo

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: Brigham and Women's Hospital

Must not be taking: Opioids, Barbiturates, SNRIs/SSRIs, others

Disqualifiers: Neuromuscular disease, Heart failure, others

Compensation: Varies

Number of Visits: 2

Duration: 2 weeks

18 Participants Needed

Trial Summary

What is the purpose of this trial?

Obstructive sleep apnea (OSA) is common and has major health implications but treatment options are limited. Some OSA patients with low arousal threshold wake up prematurely during an obstructive event and do not have time for spontaneous upper airway (UA) dilator muscle recruitment. As a consequence they are exposed to apnea and hypopnea cycling. In this protocol the investigators will test the effect of trazodone administered before sleep on OSA traits and OSA severity during sleep.

Will I have to stop taking my current medications?

The trial requires that you stop taking certain medications, including those that stimulate or depress breathing, SNRIs/SSRIs, and medications that lengthen the QTc interval. If you are on any of these, you may need to stop them to participate.

What data supports the effectiveness of the drug trazodone for obstructive sleep apnea?

Research suggests that trazodone may help improve sleep by increasing total sleep time and reducing the time it takes to fall asleep in people with insomnia. Additionally, trazodone has been shown to increase the respiratory arousal threshold in patients with obstructive sleep apnea, which might help improve breathing during sleep. ^{1 2 3 4 5}

Is trazodone generally safe for humans?

Trazodone is generally considered safe for humans, with common side effects including drowsiness, headache, dizziness, and dry mouth. It has a low risk of causing weight gain and sexual dysfunction, but may infrequently cause low blood pressure, heart rhythm changes, and rare cases of prolonged erections. It is relatively safe in overdose, but its metabolite m-CPP may have potential risks. ^{1 6 7 8 9}

How does the drug trazodone differ from other treatments for obstructive sleep apnea?

Trazodone is unique in treating obstructive sleep apnea because it increases the respiratory arousal threshold, allowing patients to tolerate higher levels of carbon dioxide during sleep, which can stabilize breathing. This is different from other treatments that may not address the arousal threshold and could potentially worsen sleep apnea in some patients. ^{1 3 7 10 11}

Eligibility Criteria

This trial is for individuals with Obstructive Sleep Apnea (OSA), particularly those who wake up too early during an obstructive event, preventing their airway muscles from responding properly. Specific eligibility criteria are not provided.

Inclusion Criteria

I have moderate-to-severe sleep apnea.

Exclusion Criteria

Hypersensitivity to the study drug (angioedema or urticaria)

Severe claustrophobia

I do not have major neurological disorders, heart failure, or other unstable conditions.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

1-2 weeks

Treatment

Participants undergo two overnight home sleep studies: one with trazodone and one with placebo, separated by a one-week washout period

2 weeks

2 visits (home-based)

Follow-up

Participants are monitored for safety and effectiveness after treatment

1 week

Treatment Details

Interventions

• Trazodone

Trial Overview The study tests the effect of Trazodone Hydrochloride, a medication given before sleep, on OSA severity and traits compared to a placebo. The goal is to see if Trazodone can improve sleep quality in OSA patients.

Participant Groups

Group I: Trazodone Experimental Treatment 1 Intervention

Trazodone capsule 30 min before sleep

Group II: Placebo Placebo Group 1 Intervention

Placebo capsule 30 min before sleep

Who Is Running the Clinical Trial?

Brigham and Women's Hospital

Lead Sponsor

Trials

1,694

Recruited

14,790,000+

Findings from Research

In a study involving 7 patients with obstructive sleep apnea (OSA), trazodone was found to increase the respiratory arousal threshold by 32%, suggesting it may help some patients with a low arousal threshold during sleep.

Despite this increase in arousal threshold, trazodone did not significantly change the apnea-hypopnea index or affect upper airway muscle activity and collapsibility, indicating that while it may offer some benefit, it is not enough to fully address the anatomical challenges of OSA.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Trazodone increases the respiratory arousal threshold in patients with obstructive sleep apnea and a low arousal threshold. Eckert, DJ., Malhotra, A., Wellman, A., et al.[2021]

Trazodone significantly improves sleep in patients with insomnia by increasing total sleep time and enhancing non-rapid eye movement stage 3 sleep, while also reducing the time it takes to fall asleep and the number of awakenings during the night, based on a meta-analysis of 11 randomized controlled trials involving 466 participants.

Despite its efficacy in improving sleep architecture, trazodone is associated with side effects such as increased daytime drowsiness and decreased appetite, indicating that it should be used cautiously in clinical settings.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Trazodone changed the polysomnographic sleep architecture in insomnia disorder: a systematic review and meta-analysis. Zheng, Y., Lv, T., Wu, J., et al.[2022]

In a study of 18 adults with obstructive sleep apnea (OSA), the combination of atomoxetine and trazodone significantly reduced the apnea-hypopnea index (AHI) and improved other sleep parameters compared to placebo, indicating better respiratory function during sleep.

The A-T combination also led to fewer apneas, less oxygen desaturation, and reduced respiratory arousals, suggesting it could be a viable alternative treatment for patients who struggle with standard OSA therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The effects of atomoxetine and trazodone combination on obstructive sleep apnea and sleep microstructure: A double-blind randomized clinical trial study. Shahbazi, M., Heidari, R., Tafakhori, A., et al.[2023]

In an 8-week study involving six depressed patients, trazodone significantly improved both depression symptoms and sleep quality, as measured by psychological evaluations and sleep monitoring.

Patients experienced a 44% reduction in sleep latency and a 14% increase in total sleep time, along with a notable improvement in sleep architecture, including a 153% increase in deep sleep (Stage IV).

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Sleep laboratory evaluation of the effects and efficacy of trazodone in depressed insomniac patients. Scharf, MB., Sachais, BA.[2013]

In a study involving 12 female patients, trazodone significantly improved sleep quality by increasing total sleep time and sleep efficiency while reducing awakenings and light sleep stages after just 7 days of treatment.

Trazodone also showed a positive effect on depression symptoms, as indicated by a reduction in the Hamilton depression rating scale scores, making it an effective option for treating insomnia associated with antidepressant use.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The effects of trazodone on sleep in patients treated with stimulant antidepressants. Kaynak, H., Kaynak, D., Gözükirmizi, E., et al.[2022]

Trazodone is an effective antidepressant for major depressive disorder (MDD) that not only alleviates depression symptoms but also effectively treats insomnia, a common issue in depression, with a favorable side effect profile compared to traditional SSRIs.

The new once-daily formulation of trazodone maintains stable blood levels for 24 hours, reducing side effects and improving treatment adherence, while its low incidence of weight gain and sexual dysfunction makes it a suitable option for many patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Role of trazodone in treatment of major depressive disorder: an update. Fagiolini, A., González-Pinto, A., Miskowiak, KW., et al.[2023]

The combination of atomoxetine and trazodone (Ato-Trazo) significantly reduced the apnea-hypopnea index in patients with obstructive sleep apnea (OSA), indicating improved severity of the condition, with a reduction from 18.2 to 7.4 events per hour (P = .024).

Unlike previous treatments, Ato-Trazo did not lower the arousal threshold, suggesting it may be better tolerated by patients, although it worsened self-reported sleep quality and further studies are needed to optimize dosage and identify the best patient subgroups.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effects of atomoxetine plus a hypnotic on obstructive sleep apnea severity in patients with a moderately collapsible pharyngeal airway. Corser, B., Eves, E., Warren-McCormick, J., et al.[2023]

Clinically significant levels of m-CPP, a harmful metabolite of trazodone, are consistently found in patients using trazodone for sleep, indicating potential safety concerns.

The risks associated with m-CPP, including serious adverse effects, outweigh the benefits of trazodone, especially considering the availability of safer alternatives developed since the 1980s.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Trazodone generates m-CPP: in 2008 risks from m-CPP might outweigh benefits of trazodone. Kast, RE.[2015]

Trazodone is an effective antidepressant that works primarily by inhibiting serotonin reuptake, showing comparable efficacy to standard antidepressants in various double-blind trials involving both inpatients and outpatients.

It has a favorable safety profile with minimal anticholinergic and cardiovascular side effects, making it a good option for patients with depression who also experience agitation, anxiety, or insomnia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Overview of USA controlled trials of trazodone in clinical depression. Feighner, JP., Boyer, WF.[2019]

In a study involving seven patients with insomnia caused by the MAO-A inhibitor brofaromine, trazodone significantly improved deep sleep and altered sleep architecture, leading to subjective reports of better sleep quality.

Trazodone was found to be safe with minimal side effects and showed no negative interactions with brofaromine, suggesting it may be an effective treatment for insomnia related to MAO-I use.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The effects of trazodone on sleep disturbances induced by brofaromine. Haffmans, PM., Vos, MS.[2022]

In a study involving 9 patients with obstructive sleep apnoea, trazodone at 100 mg significantly increased the arousal threshold during sleep, allowing patients to tolerate higher levels of carbon dioxide (CO2) before waking up.

The results suggest that trazodone may help improve breathing stability during sleep in OSA patients by increasing the effort-related arousal threshold, which could be beneficial for managing their condition.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Trazodone increases arousal threshold in obstructive sleep apnoea. Heinzer, RC., White, DP., Jordan, AS., et al.[2021]

References

1. United States pubmed.ncbi.nlm.nih.gov

Trazodone increases the respiratory arousal threshold in patients with obstructive sleep apnea and a low arousal threshold. [2021]

2. England pubmed.ncbi.nlm.nih.gov

Trazodone changed the polysomnographic sleep architecture in insomnia disorder: a systematic review and meta-analysis. [2022]

3. Netherlands pubmed.ncbi.nlm.nih.gov

The effects of atomoxetine and trazodone combination on obstructive sleep apnea and sleep microstructure: A double-blind randomized clinical trial study. [2023]

4. United States pubmed.ncbi.nlm.nih.gov

Sleep laboratory evaluation of the effects and efficacy of trazodone in depressed insomniac patients. [2013]

5. Netherlands pubmed.ncbi.nlm.nih.gov

The effects of trazodone on sleep in patients treated with stimulant antidepressants. [2022]

6. England pubmed.ncbi.nlm.nih.gov

Role of trazodone in treatment of major depressive disorder: an update. [2023]

7. United States pubmed.ncbi.nlm.nih.gov

Effects of atomoxetine plus a hypnotic on obstructive sleep apnea severity in patients with a moderately collapsible pharyngeal airway. [2023]

8. England pubmed.ncbi.nlm.nih.gov

Trazodone generates m-CPP: in 2008 risks from m-CPP might outweigh benefits of trazodone. [2015]

9. Germany pubmed.ncbi.nlm.nih.gov

Overview of USA controlled trials of trazodone in clinical depression. [2019]

10. England pubmed.ncbi.nlm.nih.gov

The effects of trazodone on sleep disturbances induced by brofaromine. [2022]

11. England pubmed.ncbi.nlm.nih.gov

Trazodone increases arousal threshold in obstructive sleep apnoea. [2021]